Following the lesioning of nerves in the peripheral or central nervous system, there is a marked increase in the expression of apolipoprotein E (apoE). Genetic studies have shown that apoE is a major risk factor for Alzheimer's disease (AD); however, the function of apoE in neuronal repair and the relationship of apoE to developing AD is unknown. One proposed function for apoE is that it scavenges lipid from degenerating processes for recycling into growing axons. Consistent with this proposed function, the PI's in vitro studies have demonstrated that apoE has a dramatic isoform specific effect on neurite outgrowth. These data suggest that apoE could play a direct role in facilitating neuronal development and axonal generation. In the proposed study, the PI will determine if the absence of apoE delays neuronal regeneration and repair in the olfactory system in vivo. His primary hypothesis is that lipid redistribution is a critical element of neuronal remodeling, and that the absence of apoE would disrupt neuronal plasticity. He will test this hypothesis by using olfactory nerve regeneration of apoE-gene deficient/knockout (apoE KO) and wild-type littermate mice as a model system. The Specific Aims are to: 1) determine the time course of apoE expression in the olfactory epithelium and bulb of mice following reversible olfactory nerve lesioning, 2) examine the recovery rate of olfactory nerves following nerve lesioning in homozygous apoE KO, heterozygous apoE KO, and wild-type littermate mice, and 3) determine the effects of aging on olfactory nerve regeneration in the three genotypes of mice. The PI will study olfactory nerve recovery in homozygous apoE KO, heterozygous apoE KO, and wild-type littermate mice following reversible lesioning with Triton X- 100 (TX). The time course of apoE expression in the olfactory epithelium and bulb of wild-type mice following lesioning will be determined by quantitative immunoblotting and confirmed with immunohistochemistry. Olfactory nerve recovery will be assessed by examining the expression of proteins that can distinguish between immature and mature phenotypes of olfactory neurons in three genotypes of mice. These studies will be performed in young (6 months) and older (20 months) animals to determine if apoE function is more important as animal's age. The PI predicts that the regeneration process will be delayed or will be incomplete in apoE KO mice compared to wild-type littermates. These studies will clarify the role of apoE on CNS neuronal plasticity, and could potentially explain the association of apoE with AD.